Protection of Macaques with Diverse MHC Genotypes against a Heterologous SIV by Vaccination with a Deglycosylated Live-Attenuated SIV Chie Sugimoto 1,2,3¤a , Satoru Watanabe 1,2¤b , Taeko Naruse 4 , Eiji Kajiwara 5 , Teiichiro Shiino 1 , Natsuko Umano 5 , Kayoko Ueda 1,2 , Hirotaka Sato 1,2 , Shinji Ohgimoto 6 , Vanessa Hirsch 7 , Francois Villinger 8,9 , Aftab A. Ansari 8 , Akinori Kimura 4 , Masaaki Miyazawa 5 , Yasuo Suzuki 3,10 , Naoki Yamamoto 1¤b , Yoshiyuki Nagai 11 , Kazuyasu Mori 1,2,3,8 * 1 AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan, 2 Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan, 3 CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan, 4 Division of Medical Science, Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan, 5 Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan, 6 Department of Virology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan, 7 Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 8 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America, 9 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America, 10 Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan, 11 Center of Research Network for Infectious Diseases, Riken, Chiyoda-ku, Tokyo Japan Abstract HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc), following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a successful HIV vaccine against diverse isolates. Citation: Sugimoto C, Watanabe S, Naruse T, Kajiwara E, Shiino T, et al. (2010) Protection of Macaques with Diverse MHC Genotypes against a Heterologous SIV by Vaccination with a Deglycosylated Live-Attenuated SIV. PLoS ONE 5(7): e11678. doi:10.1371/journal.pone.0011678 Editor: Douglas F. Nixon, University of California San Francisco, United States of America Received March 22, 2010; Accepted June 28, 2010; Published July 20, 2010 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: This work was supported by AIDS research grants from the Health Sciences Research Grants, from the Ministry of Health, Labor, and Welfare in Japan, and from the Ministry of Education, Culture, Sports, Science and Technology in Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: mori@nibio.go.jp ¤a Current address: Division of Immunology, Tulane National Primate Research Center, Covington, Louisiana, United States of America ¤b Current address: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Introduction Molecular epidemiological studies have revealed the existence of an extensive degree of diversity of HIV-1 isolates [1]. HIV-1 is classified in three major groups (M, N, O) based on their geographical origin. Group M represents the predominant HIV-1 circulating through the world and has been divided into more than 10 subtypes (clades) as well as increasing number of circulating recombinant forms (CRF) primarily due to error-prone viral reverse transcriptase and the occurrence of super-infections. This diversity is continuously expanding worldwide and is a major obstacle for the successful development of an AIDS vaccine. While the generation of a vaccine capable to prevent transmission of HIV isolates endemic in a particular area remains an unfulfilled task, protection against phylogenetically distant viruses represents an even more formidable hurdle. The failure and dismal success of HIV-1 vaccine trials that have been conducted so far has prompted a re-emphasis for more basic studies concerning vaccine PLoS ONE | www.plosone.org 1 July 2010 | Volume 5 | Issue 7 | e11678